SUN-733 Recurrent metatarsal, scapular and acromial fractures during Denosumab therapy in Adult-onset Hypophosphatasia with a pathogenic variant of the ALPL gene and a variant of uncertain significance of the ATRIP Gene

Abstract Disclosure: M. Shahid: None. J. Hufnagel: None. A. Lopez: None. C.A. Koch: None. Introduction: Hypophosphatasia (HPP) is a rare, genetic defect in bone and/or teeth mineralization caused by mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). Five forms have been identified based on the age of onset and clinical manifestations: perinatal, infantile, childhood, adult, and odontohypophosphatasia. Case: A 66-year-old white female with a history of gastric bypass and alcohol use disorder in her 40s, fibromyalgia and hypothyroidism was referred for osteoporosis. She reported bone aches since age 18y and a calcaneal and multiple metatarsal stress fractures while walking at age 59 and 60y, respectively. She was initially started on risedronate at age 61y but due to continued non-traumatic metatarsal fractures teriparatide was recommended. Teriparatide was not covered by insurance, therefore, denosumab was started. Despite 4y of Denosumab she continued to have metatarsal fractures, in addition to rib, acromial and scapular fractures. No active secondary causes to trigger bone loss were identified. Bone density scan showed T-scores of 0.0, -1.6, and -1.2 at spine, femoral neck, and total hip, respectively. She was found to have low ALP ranging from 28-39 IU/L (N: 37-153) for at least 7 y, low bone-specific ALP of 5.4 mcg/L (N: 5.6-29) and high vitamin B6 at 31.6 ng/mL (N: 2.1-21.7) suggesting HPP. Genetic analysis showed a pathogenic mutation in Exon 7 c.746G>T of the ALPL gene and a variant of uncertain significance in Exon 12 of the ATRIP gene confirming HPP. She has been offered treatment with Asfotase alfa (AA). Discussion: Adult-onset HPP was recognized in a 66-yo female who presented with acromial, scapular and recurrent metatarsal fractures while on denosumab therapy for 4 y for osteoporosis. HPP is an under-recognized disorder that presents with extreme variability with respect to age of onset and clinical features such as impaired skeletal mineralization, recurrent fractures, impaired growth and mobility, and premature tooth loss. Fragility fractures are mistakenly diagnosed as osteoporotic and are treated with antiresorptive drugs which further increases the fracture risk as demonstrated in our case. Low serum ALP, low bone-specific ALP and high serum vitamin B6 levels suggest the diagnosis of HPP, confirmed by identifying a mutation in the ALPL gene. Our case further illustrates the broad spectrum of phenotype and genotype, as there also was a variant of uncertain significance in the ATRIP gene which currently has no well-established disease association. However, there is preliminary data supporting correlation with Seckel syndrome - a microcephalic osteodysplastic dwarfism. AA, a human recombinant enzyme replacement therapy was approved for HPP in 2015. Treatment with anabolic agents such as teriparatide and romosozumab has been reported while anti-resorptives such as bisphosphonates and denosumab are contraindicated. Presentation: Sunday, July 13, 2025